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Article: Unique molecular characteristics of NAFLD-associated liver cancer accentuate β-catenin/TNFRSF19-mediated immune evasion

TitleUnique molecular characteristics of NAFLD-associated liver cancer accentuate β-catenin/TNFRSF19-mediated immune evasion
Authors
KeywordsHepatocellular carcinoma
immune escape
NAFLD
somatic variants
βCatenin
Issue Date26-Mar-2022
PublisherElsevier
Citation
Journal of Hepatology, 2022, v. 77, n. 2, p. 410-423 How to Cite?
Abstract

Background & Aims

The hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), can lead to the development of hepatocellular carcinoma (HCC). Despite a strong causative link, NAFLD-HCC is often underrepresented in systematic genome explorations.

Methods

Herein, tumor-normal pairs from 100 patients diagnosed with NAFLD-HCC were subject to next-generation sequencing. Bioinformatic analyses were performed to identify key genomic, epigenomic and transcriptomic events associated with the pathogenesis of NAFLD-HCC. Establishment of primary patient-derived NAFLD-HCC culture was used as a representative human model for downstream in vitro investigations of the underlying CTNNB1 S45P driver mutation. A syngeneic immunocompetent mouse model was used to further test the involvement of CTNNB1mut and TNFRSF19 in reshaping the tumor microenvironment.

Results

Mutational processes operative in the livers of patients with NAFLD inferred susceptibility to tumor formation through defective DNA repair pathways. Dense promoter mutations and dysregulated transcription factors accentuated activated transcriptional regulation in NAFLD-HCC, in particular the enrichment of MAZ-MYC activities. Somatic events common in HCCs arising from NAFLD and viral hepatitis B infection underscore similar driver pathways, although an incidence shift highlights CTNNB1mut dominance in NAFLD-HCC (33%). Immune exclusion correlated evidently with CTNNB1mut. Chromatin immunoprecipitation-sequencing integrated with transcriptome and immune profiling revealed a unique transcriptional axis, wherein CTNNB1mut leads to an upregulation of TNFRSF19 which subsequently represses senescence-associated secretory phenotype-like cytokines (including IL6 and CXCL8). This phenomenon could be reverted by the Wnt-modulator ICG001.

Conclusions

The unique mutational processes in the livers of patients with NAFLD and NAFLD-HCC allude to a “field effect” involving a gain-of-function role of CTNNB1 mutations in immune exclusion.

Lay summary

The increasing prevalence of metabolic syndrome in adult populations means that NAFLD is poised to be the major cause of liver cancer in the 21st century. We showed a strong “field effect” in the livers of patients with NAFLD, wherein activated β-catenin was involved in reshaping the tumor-immune microenvironment.


Persistent Identifierhttp://hdl.handle.net/10722/331892
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWong, AM-
dc.contributor.authorDing, XF-
dc.contributor.authorWong, AM-
dc.contributor.authorXu, MJ-
dc.contributor.authorZhang, LY-
dc.contributor.authorLeung, HHW-
dc.contributor.authorChan, AWH-
dc.contributor.authorSong, QX-
dc.contributor.authorKwong, J-
dc.contributor.authorChan, LKY-
dc.contributor.authorMan, MT-
dc.contributor.authorHe, M-
dc.contributor.authorChen, JN-
dc.contributor.authorZhang, Z-
dc.contributor.authorYou, WX-
dc.contributor.authorLau, C-
dc.contributor.authorYu, AL-
dc.contributor.authorWei, YY-
dc.contributor.authorYuan, YF-
dc.contributor.authorLai, PBS-
dc.contributor.authorZhao, JM-
dc.contributor.authorMan, K-
dc.contributor.authorYu, J-
dc.contributor.authorKahn, M-
dc.contributor.authorWong, NTL-
dc.date.accessioned2023-09-28T04:59:25Z-
dc.date.available2023-09-28T04:59:25Z-
dc.date.issued2022-03-26-
dc.identifier.citationJournal of Hepatology, 2022, v. 77, n. 2, p. 410-423-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/331892-
dc.description.abstract<h3>Background & Aims</h3><p>The hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), can lead to the development of hepatocellular carcinoma (HCC). Despite a strong causative link, NAFLD-HCC is often underrepresented in systematic genome explorations.</p><h3>Methods</h3><p>Herein, tumor-normal pairs from 100 patients diagnosed with NAFLD-HCC were subject to next-generation sequencing. Bioinformatic analyses were performed to identify key genomic, epigenomic and transcriptomic events associated with the pathogenesis of NAFLD-HCC. Establishment of primary patient-derived NAFLD-HCC culture was used as a representative human model for downstream <em>in vitro</em> investigations of the underlying <em>CTNNB1</em> S45P driver mutation. A syngeneic immunocompetent mouse model was used to further test the involvement of <em>CTNNB1</em><sup>mut</sup> <em>and TNFRSF19</em> in reshaping the tumor microenvironment.</p><h3>Results</h3><p>Mutational processes operative in the livers of patients with NAFLD inferred susceptibility to tumor formation through defective DNA repair pathways. Dense promoter mutations and dysregulated transcription factors accentuated activated transcriptional regulation in NAFLD-HCC, in particular the enrichment of MAZ-MYC activities<em>.</em> Somatic events common in HCCs arising from NAFLD and viral hepatitis B infection underscore similar driver pathways, although an incidence shift highlights <em>CTNNB1</em><sup>mut</sup> dominance in NAFLD-HCC (33%). Immune exclusion correlated evidently with <em>CTNNB1</em><sup>mut</sup>. Chromatin immunoprecipitation-sequencing integrated with transcriptome and immune profiling revealed a unique transcriptional axis, wherein <em>CTNNB1</em><sup>mut</sup> leads to an upregulation of <em>TNFRSF19</em> which subsequently represses senescence-associated secretory phenotype-like cytokines (including <em>IL6</em> and <em>CXCL8</em>). This phenomenon could be reverted by the Wnt-modulator ICG001.</p><h3>Conclusions</h3><p>The unique mutational processes in the livers of patients with NAFLD and NAFLD-HCC allude to a “field effect” involving a gain-of-function role of <em>CTNNB1</em> mutations in immune exclusion.</p><h3>Lay summary</h3><p>The increasing prevalence of metabolic syndrome in adult populations means that NAFLD is poised to be the major cause of liver cancer in the 21st century. We showed a strong “field effect” in the livers of patients with NAFLD, wherein activated β-catenin was involved in reshaping the tumor-immune microenvironment.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofJournal of Hepatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectHepatocellular carcinoma-
dc.subjectimmune escape-
dc.subjectNAFLD-
dc.subjectsomatic variants-
dc.subjectβCatenin-
dc.titleUnique molecular characteristics of NAFLD-associated liver cancer accentuate β-catenin/TNFRSF19-mediated immune evasion-
dc.typeArticle-
dc.identifier.doi10.1016/j.jhep.2022.03.015-
dc.identifier.scopuseid_2-s2.0-85131354541-
dc.identifier.volume77-
dc.identifier.issue2-
dc.identifier.spage410-
dc.identifier.epage423-
dc.identifier.isiWOS:000837192900021-
dc.identifier.issnl0168-8278-

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